Visible-light-promoted oxidative halogenation of alkynes

Article abstract of DOI:10.1039/c9cc07655g

In nature, halogenation promotes the biological activity of secondary metabolites, especially geminal dihalogenation. Related natural molecules have been studied for decades. In recent years, their diversified vital activities have been explored for treating various diseases, which call for efficient and divergent synthetic strategies to facilitate drug discovery. Here we report a catalyst-free oxidative halogenation achieved under ambient conditions (halide ion, air, water, visible light, room temperature, and normal pressure). Constitutionally, electron transfer between the oxygen and halide ion is shuttled via simple conjugated molecules, in which phenylacetylene works as both reactant and catalyst. Synthetically, it provides a highly compatible late-stage transformation strategy to build up dihaloacetophenones (DHAPs).

Full text of DOI:10.1039/c9cc07655g

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Visible-light-promoted oxidative halogenation of
alkynes†
Yiming Li,‡a Tao Mou,‡a Lingling Lua and Xuefeng Jiang
Cite this: Chem. Commun., 2019,
55, 14299
abc
*
Received 30th September 2019,
Accepted 22nd October 2019
DOI: 10.1039/c9cc07655g
rsc.li/chemcomm
In nature, halogenation promotes the biological activity of secondary
metabolites, especially geminal dihalogenation. Related natural
molecules have been studied for decades. In recent years, their
diversified vital activities have been explored for treating various
diseases, which call for efficient and divergent synthetic strategies
to facilitate drug discovery. Here we report a catalyst-free oxidative
halogenation achieved under ambient conditions (halide ion,
air, water, visible light, room temperature, and normal pressure).
Constitutionally, electron transfer between the oxygen and halide
ion is shuttled via simple conjugated molecules, in which phenyl-
acetylene works as both reactant and catalyst. Synthetically, it
provides a highly compatible late-stage transformation strategy to
build up dihaloacetophenones (DHAPs).
Halogenase plays a significant role in metabolic processes, and
produces a mass of important halide-containing secondary
metabolites with unique bioactivities, including several effective
drugs.1,2 Among biogenic halogenated molecules (45000),3 there
are more than 180 geminal dichloro- and 70 geminal dibromo-
molecules. In particular, the ones with pharmaceutical data
account for up to 57%.4 In addition, more and more artificial
geminal dihalo-compounds have been developed against serious
Fig. 1 Significant geminal dihalo-compounds.
diseases.5 It is noteworthy to highlight that, recently, the simple modulation of lipophilicity and nonspecific hydrophobic inter-
dichloroacetophenone was exploited to inhibit the activity of action with protein targets, but also to the formation of directional
pyruvate dehydrogenase kinase 1, an important target in cancer intermolecular interaction with proteins.2 Urgent demand from
studies6 (Fig. 1). In principle, the key functions of halogens upon pharmaceutical studies necessitates fast and highly tolerated
bioactivity and bioavailability are attributed not only to the synthetic strategies.
Naturally, haloperoxidases and halogenases produce dihalo-
acetophenones (DHAPs) with inorganic halogen salts (Fig. 2a).
Conventionally, DHAPs were constructed via halogenation of
acetophenones and phenylacetylenes via corrosive and low-
a Shanghai Key Laboratory of Green Chemistry and Chemical Process, East China
Normal University, 3663 North Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: xfjiang@chem.ecnu.edu.cn
compatible molecular halogens.7 Then, various electrophilic
halogen sources mostly with polyamide backbones were
utilized,8 such as NBS,9 NCS,10 etc.11 but with tedious workup
and lower atom-efficiency. Recently, halide ions have been
employed instead of electrophilic halogen sources. Paradoxically,
halide ions are commonly inactive unless with strong oxidants,
which makes sensitive functional groups incompatible (Fig. 2b).12
b State Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic
Chemistry Chinese Academy of Sciences, Shanghai, 200032, P. R. China
c State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin,
300071, P. R. China
† Electronic supplementary information (ESI) available. CCDC 1915404. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c9cc07655g
‡ These authors contributed equally.
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Fig. 3 Compatibility of oxybromination. * 10 mmol scale, 56%, 1.54 g.
† 2 h.
Fig. 2 The synthesis of dihaloacetophenones.
To mimic mild natural synthesis, a revealing photocatalytic strategy
13
¨
was developed by Konig et al., utilizing riboflavin tetraacetate were tested, which obtained good to excellent yields (4–36).
instead of flavin adenine dinucleotide as the catalyst and p-methoxy The transformable halogens (4–6, 13–15), nitro- (7), cyano (8),
benzyl alcohol instead of nicotinamide adenine dinucleotide II ester (17), and even phosphamide (18) groups were tolerated. In
(NADH2) as a reductant. For enhancing the reactivity, hydrochloric addition, the oxidatively sensitive heteroaromatic and strained
acid (HCl) and trifluoroacetic acid were employed as chloride rings, such as thiophenyl (22), furanyl (23), pyridinyl (24), and
source and promoter (Fig. 2c). Essentially, the core of enzyme- cyclopropanyl (25), were investigated and found to be well
catalyzed and biomimic halogenation is the electron transfer from tolerated. Moreover, the internal alkynes were also successfully
the halide anion to oxygen, which generates active halogen and tranformed under these mild conditions (26–36). The gram-scale
oxygen species followed by introduction of halogen atoms. How- reaction was realized in moderate yield (2). Meanwhile, oxychloro-
ever, to the best of our knowledge, no direct way has been reported, molecules construction is also shown in Fig. 4 (3, 37–55). Generally,
particularly under ambient conditions, especially with halide electronic properties and steric hindrance of substituents did not
ions,14 air, water, room temperature, normal pressure, and visible affect its efficencies. Halogens (F, Cl, Br) (39–41, 43, 47, 48, 55),
light. Here, photoredox15 oxyhalogenation with phenylacetylene cyano (50), sensitive thiophenyl (51) and cyclopropanyl (53) groups
without extra catalyst16 was introduced (Fig. 2d).
are tolerated. Notably, the internal alkynes were also well converted.
The spectrum of UV-visible light absorption showed that Aliphatic acetylenes with photon absorption groups worked as well
phenylacetylene possesses weak absorption even in 0.1 M but with low efficiency.
concentration (ESI,† Section III-1). However, detailed mecha-
Last-stage oxyhalogenations were carried out on molecules
nistic analyses and experimental screening found that a with high complexity (Fig. 5). Natural motifs such as menthol (56),
Brønsted acid played an important role in enhancing the camphor (57), amino ester (58), and saccharides (59 and 60) were
activity of oxybromonation, especially when the light energy found to be tolerated. Moreover, multisubstituted pyridine (61)
was confined into a small space (ESI,† Section IV), in which was also well preserved. An important geminal dichloro-drug
NaHSO4ÁH2O was the most efficient one (Table S1, entries 1–4, Mitotan, treating adrenocortical carcinoma and Cushing’s
ESI†). Other bromide sources, such as KBr, LiBr, NH4Br, and syndrome, was easily achieved with its analogous library,
MgBr2, did not perform better (Table S1, entries 5–8, ESI†). relying on the abundance of alkynes and excellent compatibility
With similar conditions and LiCl as a chloro-source, the of this strategy (62–64).
corresponding geminal dichloronation was realized as well
(Table S2, ESI†).
Further mechanistic studies were carried out to disclose the
essences of this strategy. First, possible active halogen species
Under optimized conditions, the generality of this strategy were explored. Phenylacetylene was confirmed as a photosensor
was comprehensively examined. For oxybromination (Fig. 3), according to UV-visible absorption spectra, which supplied
functional groups with electron-withdrawing and electron- energy for the subsequent electron transfer (ESI,† Section III-1).
donating groups on different positions of the aromatic rings Fluorescent quenching experiments were conducted, showing
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active phenylacetylene and bromide anions instead of oxygen.
Furthermore, radical trapping experiments of compound 69
only afforded acyclic product 70 instead of cyclic products,
implying that the active halogenation species reacted with
phenylacetylene may not be a bromo-radical but a bromine
cation (ESI,† Section III-4), which is an important species in
enzyme-involved halogenations.1–3 In short, it is suggested that
the bromide anion was oxidized to radicals by acitive phenyl-
acetylene, and then to a bromine cation with the assistance of
in situ generated oxidants.
Afterward, the active oxidant in this system was surveyed. The
yields of reaction barely changed with active oxygen inhibitors,
such as singlet oxygen (1O2) inhibitors (NaN3, 1,3-diphenyliso-
À
benzofuran), superoxide radical (O2 ꢀ) inhibitors (1,3-diphenyliso-
benzofuran), and hydroxy radical (ꢀOH) inhibitor (tBuOH) (ESI,†
Section III-5). Moreover, electron paramagnetic resonance (EPR)
À
ꢀ
reactions with DMPO (trapping reagents of O2 and ꢀOH) and
1
TEMP (trapping reagents of O2) showed no radical signals (ESI,†
Section III-6). Afterward, quantitative iodometric experiments
detected the presence of hydrogen peroxide (0.112 mmol) even
after the completion of transformation (ESI,† Section III-7). Con-
sidering the highly oxidative potential of phenylacetylene, it is
suggested that active phenylacetylene and H2O2 instead of 1O2,
Fig. 4 Compatibility of oxychlorination.
À
ꢀ
O2 ꢀ, and OH might be the active oxidants that convert bromo
radicals to bromine cations.
Subsequently, the origin of the oxygen atom in the products was
analyzed. A control experiment without oxygen failed to afford 2,
implying the necessity of oxygen (ESI,† Section III-10, entry 1). The
reaction with only 18O2 afforded 2 with fully 18O-labelled product,
albeit with only 10% yield (ESI,† Section III-10, entry 2). Product 2
was partially labelled when H2O18 was used instead of H2O16
(ESI,† Section III-10, entry 3). When both H2O18 and 18O2
were introduced together, complete labelling occurred (ESI,†
Section III-9, 10). The above results demonstrated that oxygen
atoms in the products mainly originated from water which
might come from oxygen partially.
Based on the above control experiments, the possible process of
this oxyhalogenation is proposed as below (ESI,† Section III-11):
initially, phenylacetylene is activated via visible light, and then
accepts an electron from a halide anion generating phenylacetylene
anion radical A and a halide radical. Oxidation of radical A by air
was assisted by protons, generating hydrogen peroxide and water,
and then regenerated ground-state phenylacetylene. Consequently,
the halide radical was oxidized to a halide cation by active starting
materials or hydrogen peroxide. Subsequent nuclephilic addition
between the halide cation and 1 produced halonium B, which
Fig. 5 Late-stage geminal dihalogenation. * 2 h.
that NaBr instead of NaHSO4 functions with phenylacetylene. was attacked by water and produced the desired product after
In addition, the corresponding quenching effort based on HBr, proton release. Mostly, no obvious monohaloketones were observed
possibly generated in situ from NaBr and NaHSO4, was more during transformation, and the prepared monohaloketones
efficient (ESI,† Section III-2). Radical trapping experiments with cannot produce desired dihaloketone. Hence, monohaloketones
TEMPO suggested the possible existence of bromide radicals were not considered as intermediates.
via the detection of TEMPO-Br via LCMS (ESI,† Section III-3).17
Inspired by the halogenase enzyme, an oxyhalogenation
Considering the reductive potential of oxygen under acidic strategy was accomplished under ambient conditions (inorganic
conditions (E0 = 1.47 V vs. SCE),18 which is lower than that of halide sources, air, water, visible light, room temperature, and
phenylacetylene (Ep/2 = 2.27 V vs. SCE in CH3CN), the reaction normal pressure). A novel halogenation mode, directly utilizing
was proposed to be initiated via an electron transfer between substrate as a catalyst for shuttling electrons between oxygen and
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We are grateful for financial support provided by the
National Key Research and Development Program of China
(2017YFD0200500), NSFC (21971065, 21722202, 21672069), the
S&TCSM of Shanghai (Grant 18JC1415600), Professor of Special
Appointment (Eastern Scholar) at Shanghai Institutions of
Higher Learning, and the National Program for Support of
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